ClinVar

Description

The p.T277I variant (also known as c.830C>T), located in coding exon 8 of the PTEN gene, results from a C to T substitution at nucleotide position 830. The threonine at codon 277 is replaced by isoleucine, an amino acid with some similar properties. This variant was reported as de novo (unconfirmed parentage) in a female child followed from birth to age 4 who presented with macrocephaly followed by patent ductus arteriosus, nevus flammeus of the philtrum suggestive of Megalencephaly-Capillary Malformation syndrome, overgrowth, widespread capillary malformations, enlarged cerebral ventricles identified by MRI and speech support was needed for learning disabilities (Busa T et al. Eur J Paediatr Neurol, 2015 Mar;19:188-92). In addition, RNA studies was performed for this variant and no abnormal splicing was reported to be associated (Wai HA et al. Genet Med, 2020 Jun;22:1005-1014). However, in a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was reported to be in the hypomorphic range of functionally abnormal (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.